Immunological memory is responsible for the long-lasting host protection against previously exposed infectious agents. The broad objective of this proposal is to understand the mechanism by which memory T cells are generated and maintained. It is hypothesized that proliferation is required for the development, survival, and function of memory T cells. This hypothesis is based on the observation that both antigen- and lymphopenia-induced proliferation lead to the generation of memory T cells, and once memory cells are formed, they continuously undergo low-level proliferation. Genes that either inhibit proliferation of mediate proliferation-promoting signals will be directly introduced into naive or memory T cells to alter their proliferation behaviors. This will be achieved by using a newly developed lentivirus-based gene transfer system. Analysis on modified cells will be conducted both in vitro and in vivo with emphasis on three specific aims 1) role of antigen- and cytokine-induced naive T cell proliferation in the development of memory T cells, 2) role of cytokine-induced memory cell proliferation in the survival and function maintenance of memory T cells, 3) relationship between proliferation and chromatin remodeling at effector cytokine loci. Findings from proposed studies will provide a basis for new vaccine development.